Angiogenesis is the formation of new blood vessels from existing structures and is involved in the regulation of wound repair and the pathobiology of numerous disease states including solid tumor growth. Because angiogenesis is regulated by a complex interaction of receptor mediated signals modified by the activities of growth factors, cytokines, proteinases, lipid and components of the extracellular matrix, it sis important for institutions with a focus on angiogenesis to include experimental programs in these and other areas such as mechanisms and intracellular traffick. As a result, this application requests support from the IDeA Program to establish a COBRE in Angiogenesis and involves the collaborative interests of a group of four new (non-R01 funded) and two established investigators at the newly formed (1998) Center for Molecular Medicine at the Maine Medical Center. The theme focuses on Signaling Paradigms in Angiogenesis as a result of the long term research interests of the Program's PI in the biology of the endothelial cell at the cellular and molecular level and the institutional commitment to support a program in Angiogenesis. The motives for this application include the use of this award to (i) support promising young independent investigators in this field, (ii) expand existing institution resources to create a larger critical mass of mechanism-oriented junior and senior investigators in this area, investigator needs and (iv) provide resources requisite for the establishment of an internationally recognized non-profit research institution in the broad area of mechanistic Vascular Biology. The application is comprised of five projects which were chosen in the field of angiogenesis and the areas of interest include the mechanisms of (i) cooperativity between FGF and Jagged 1 signaling in the regulation of chord formation and in the regulation of a stable collateral circulatory system following ischemic heart damage, (ii) the antagonism of FGFR signaling and the regulation of branching by Sprouty, (iii) inflammatory- mediated release of FGF2 as a covalent complex with plasminogen fragments in vivo, (iv) the TGFbeta-receptor-associated protein, endoglin, to mediate arteriovenous malformations and (v) Twist as a transcriptional mediator of tubulogenesis. Program expansion by 2001 will include the recruitment of six investigators with genetic, cellular, and molecular signaling expertise mediated by (i) proteinases and their inhibitors, (ii) extracellular matrix, (iii) cadherins, (iv) VEGF in lymphogenesis and angiogenesis, (v) G-protein-coupled receptors and (vi) intracellular trafficking but the resources from this award will only be used for Program expansion in areas (i) and (ii). It is anticipated that this award will not only enable the Ctr. for Mol. Med. to achieve its goal at a more rapid and efficient rate but the insight derived from these investigators may significantly impact the fields of Angiogenesis and Vascular Biology.